In our past studies we uncovered several lupus susceptibility genes that, either by themselves or by interacting with a variety of other genetic factors, modify both the induction and progression of autoimmune disease. We previously determined that mice deficient in the IgG receptor Fc&#947;RIIB develop spontaneous anti-nuclear antibodies and fatal glomerulonephritis. Characterization of other genetic modifiers of lupus in the Fc&#947;RIIB-deficient mouse model allowed us to determine that a mere duplication of the Tlr7 gene is sufficient to agravate autoimmune disease. We showed, using transgenic overexpression of TLR7, that TLR7 is essential to regulate autoimmunity and prevent dendritic cell expansion. These mice provide a prime example of how important it is to control the expression of innate receptors. These studies provide a theoretical framework in which anti-viral innate responses, when not properly regulated, can result in autoreactivity and lethal inflammatory disease. We have expanded these studies to include other anti-viral pathways such as the RNA-sensor MDA5 in the initiation of systemic autoimmune disease. Our characterization of the lupus-prone Fc&#947;RIIB-deficient mouse strain has also allowed us to study correlation between autoimmune susceptibility and resistance to pathogen infection. On one hand, we have observed that certain viral infections can delay the onset of autoimmune disease: mice infected with VSV are less likely to generate spontaneous autoreactive responses. On the other hand, we have determined that a lupus-prone background confers selective advantage for resistance to lethal cerebral malaria. We expect that these studies will help dissect the requirements for autoimmune pathology and will address the effect of pathogen infections in overall incidence of autoimmune disease. Newly discovered genes will possibly uncover potential routes for modifying ongoing disease in lupus or other autoimmune diseases and will serve as predictors of disease susceptibility, progression and severity.